Autism is a neurodevelopmental abnormality characterized by significant disturbances in social, communicative, and behavioral functioning. Epidemiologic data has implicated a strong genetic component in autism. The International Molecular Genetic Study of Autism Consortium (IMGSAC) first reported significant results for markers in the region 7q31-35, with a peak maximum lod score (MLS) of 3.55, for their genomic autism screen. Since these initial results, multiple groups, ours included, have reported supporting evidence for an autism locus (or loci) on the long arm of human chromosome 7. Additional support in our data comes from a multiplex autism family (Duke 7543) with a cytogenetic abnormality (Inv (7)(q22q31.2)) overlapping the region of potential linkage as well as other individuals with cytogenetic abnormalities on 7q and autism. During the past three years we have mapped and investigated candidate genes that lie in the critical autism region. Despite this convergence of linkage and cytogenetic studies and efforts by numerous groups, definitive identification of the chromosome 7q gene has remained elusive. In order to identify this gene we propose an integrated yet multiprong approach. First, we will fine map, haplotype, and carry out association studies on the 15 MB to either side of the peak linkage signal for autism using a SNP each 100kb (total 300 SNPs) in 391) multiplex autism families (approximately 1600} individuals available at the start of this project). We will do the bulk of this high-density SNP mapping using newly developed primer extension protocols using pooled patient DNA in conjunction with DHPLC. Candidate genes that lie within peak SNP regions (p<= 0.05) will then be evaluated within the entire data set including singleton families. Secondly, we will simultaneously evaluate and carry out association studies and molecular analyses of genes surrounding the breakpoints in family 7543. Lastly, we will thorougl_y evaluate other proposed chromosome 7q candidate genes, beginning with the reelin gene, for which we have recently obtained significant evidence for association in the joint DUMC, AGRE and Boston/VUMC dataset. All candidate genes will be evaluated by haplotype mapping studies, mutational analysis, transcription and expression as well as methylation and cytogenetic abnormalities. Using this systematic and integrated approach will allow us to ultimately identify the chromosome 7 autism gene, representing a fundamental step forward in solving the genetic riddles of autism.